Percutaneous delivery system

ABSTRACT

The invention relates to a substantially homogenous liquid composition capable of percutaneous delivery of one or more physiologically active agents, the composition including a rate modulating polymer, a volatile solvent and at least one physiologically active agent, said rate modulating polymer being selected to enable modulation of the rate of delivery of said physiologically active agent. Methods of percutaneous delivery of active agents and of prophylactic or therapeutic antimicrobial, antifungal or antiviral treatment using the compositions of the invention are also described.

FIELD OF THE INVENTION

The present invention is concerned with a system suitable for thepercutaneous delivery, particularly transdermal delivery of activeagent. The invention also relates to a method of percutaneous deliveryof actives and to therapeutic or prophylactic methods of treatment of asubject by percutaneous delivery of an active agent.

BACKGROUND TO THE INVENTION

The term “active agent” as used herein is intended to denote substancesthat have a physiological effect, for example, a drug. The term“homogenous” as used herein is intended to mean uniform throughout. Theterm “film forming” as used herein is intended to mean a substancecapable of forming a thin layer on the surface to which it is appliedand when exposed to ambient conditions. The term “liquid” as used hereinis intended to mean a substance which is flowable. The term“percutaneous” as used herein is intended to mean any route ofadministering an active agent onto, into or through the skin of asubject so as to achieve one or more of a topical, local or systemicphysiological effect.

The use of the skin as a route for delivery of drugs is of relativelyrecent origin. One form of delivery system is that based on the use ofan adhesive transdermal patch. These transdermal patches provide analternative non-invasive parenteral route for the delivery of drugswhich may or may not be suitable for oral administration. An example ofan early form of a transdermal patch is described in U.S. Pat. No.3,598,122 where the patch is in the form of a bandage.

Conventional routes of drug administration suffer several disadvantageswhen compared to the percutaneous route of drug administration. Thepercutaneous route of delivery may allow for the controlled release ofan active agent into the systemic circulation. Many drugs are poorlyabsorbed by traditional routes of delivery and it has been found thatthe percutaneous route provides an effective method of achievingimproved bioavailability for those active agents.

Examples of the uses of transdermal patches include treatment ofnicotine addiction using nicotine containing patches, hormonereplacement therapy, treatment of travel sickness using hyoscine, anginausing glyceryltrinitrate, treatment of rheumatism using flurbiprofen oribuprofen, and intractable pain relief using fentanyl. Other examples oftransdermal patches are clonidine patches for vasoconstrictor therapyand treatment of migraine (see, for example, U.S. Pat. No. 4,201,211),oestradiol patches for treatment of osteoporosis,oestradiol/norethisterone patches, and oestrogen/progesterone patches.The world therapeutic patch market is expected to increase significantlyover the next few years.

Existing transdermal patches usually comprise a layer including theactive and an adhesive layer and rely on the adhesive layer forattachment of the patch to the skin of a subject. This delivery systeminvolves incorporation of the medicament into a carrier such as apolymeric matrix and/or pressure-sensitive adhesive formulation. Theadhesive must adhere to the skin and permit migration of the medicamentfrom the carrier through the skin into the bloodstream of the subject.The medicament may be included in the polymeric matrix or the adhesivelayer or both.

An example of an adhesive transdermal delivery system is described inAustralian patent 670033. This patent describes a dermal compositioncomprising a blend of a polyacrylate and a second polymer selected frompolysiloxane or a hydrocarbon polymer, wherein the polyacrylate and thesecond polymer are mutually insoluble or immiscible polymers and a drugwherein the composition is a pressure-sensitive adhesive.

Adhesive based transdermal systems suffer a number of disadvantages. Amajor disadvantage is that the adhesive is responsible for an adverseskin reaction in about 30% of individuals. Current skin patches areocclusive and prevent the skin from transpiring. Moreover the skin areato which the adhesive patch may be applied is restricted to a non-hairyarea of the skin that is substantially free of wrinkles, crease andfolds. Furthermore, the wearer of an adhesive patch is aware of itspresence because of the its inability to stretch with the skin on bodymovement.

In a related art there exist topical creams for delivery of activeagents for treatment of certain skin diseases. One such disclosure isthat of U.S. Pat. No. 4,935,241 in the name of SHIONOGI & CO LTD. Thispatent describes a pharmaceutical formulation for localised treatment oftinea pedis which comprises a topical cream including an active agentand an ethyl acrylate-methyl methacrylate copolymer.

An objective of the present invention is to provide a system for thepercutaneous delivery of one or more active agents which system avoids,or mitigates at least in part, one or more of the disadvantagesattending prior art adhesive transdermal patches. In particular, thecompositions developed should be non-occlusive, rate variable andeffective in delivering an active agent to have a systemic, topical orlocal effect upon a subject.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides, in one aspect, asubstantially homogenous liquid composition capable of percutaneousdelivery of one or more physiologically active agents, the compositionincluding at least one rate modulating polymer, a volatile solvent andat least one physiologically active agent, said rate modulating polymerbeing selected to enable modulation of the rate of delivery of saidphysiologically active agent.

An advantage of the present invention is that the composition of theinvention can be dispensed onto, and rubbed into the skin of a subjectto form a thin film on the skin surface, this film providing for thepercutaneous delivery of the one or more actives contained in thecomposition. The composition may be applied to the selected skin surfaceof skin and rubbed onto the skin until a suitable thickness of film isformed. Unlike conventional transdermal patches, the transdermal systemof the present invention does not require the use of an adhesive layer.Moreover, it is robust (resistant to accidental removal), waterproof andhas good substantivity on the skin. It has additionally been found thatthe formulations according to the invention can be varied by alteringthe nature of the modulating polymer to alter the rate of release of theactive agent into the skin of the patient. In particular it is foundthat the use of the modulating polymer enables the formation of areservoir of active agent on the skin of the patient which can beabsorbed by the skin at a varying rate depending on the other componentsof the formulation.

Although it is preferred that the skin surface be non-hairy, thepresence of hair does not create as significant a problem as is the casewith adhesive patches. Similarly the presence of wrinkles, creases andfolds in the skin are not an impediment to the application of thecomposition of the invention to a particular area of the body, althoughit is preferable to avoid areas that have significant creasing or folds.Moreover the film that is formed is unobtrusive to the subject in thatthe subject is not significantly aware of its presence on the skin.

The composition according to the invention may also preferably include asecond polymer which may be of opposite water affinity to the firstpolymer. For example, where the first polymer is hydrophobic, the secondpolymer may be hydrophilic and vice versa. The percutaneous compositionof the invention preferably includes at least one hydrophobic polymerand at least one hydrophilic polymer, one of which is selected to enablemodulation of the rate of delivery of said physiologically active agent.

Where a hydrophobic polymer and a hydrophilic polymer are used, thecomposition may be such that when applied to the skin, the volatilesolvent may evaporate leaving a two-phase film. The formed film mayinclude a continuous phase and a dispersed phase. The hydrophilicpolymer may form the continuous phase and the hydrophobic polymer mayform the disperse phase in the formed film, or vice versa.

Alternatively, the hydrophilic polymer may be soluble in the hydrophobicpolymer, or vice versa so that when the volatile solvent evaporates uponapplication of the composition to the patients skin, the remaining filmis a single phase.

Where the composition of the invention is used to form a two phase film,the active agent may be contained in the continuous phase of the film orin the disperse phase, or in both phases. It is thought that theinclusion of the active agent in the continuous phase of a formed filmhas the effect of increasing the release rate of the active whereasincluding the active in the dispersed phase slows down its rate ofrelease.

In another aspect of the invention, there is provided a substantiallyhomogenous liquid composition capable of percutaneous delivery of one ormore physiologically active agents, the composition including a volatilesolvent, at least one physiologically active agent and at least twopolymers, one of which is water soluble, and one of which is selected toenable modulation of the rate of delivery of said physiologically activeagent.

The second polymer may be of opposite water affinity to the firstpolymer. For example, where the first polymer is hydrophobic, the secondpolymer may be hydrophilic and vice versa. The percutaneous compositionof the invention preferably includes at least one hydrophobic polymerand at least one hydrophilic polymer, one of which is selected to enablemodulation of the rate of delivery of said physiologically active agent.

In a particularly preferred aspect, the present invention provides asubstantially homogenous liquid composition capable of percutaneousdelivery of one or more active agents, the composition including ahydrophilic polymer and an alkyl olefinic acid amide/olefinic acid orester copolymer, at least one active agent and a volatile solvent forsaid hydrophilic polymer and said copolymer and optionally for the saidat least one active.

In another aspect of the invention, there is provided a substantiallyhomogenous liquid composition capable of percutaneous delivery of one ormore physiologically active agents, the composition including a volatilesolvent, at least one physiologically active agent, at least onemodulating polymer and a thickening agent, said at least one modulatingpolymer being selected to enable modulation of the rate of delivery ofsaid physiologically active agent and said thickening agent excludingethyl cellulose. Preferably said thickening agent is soluble in bothwater and alcohol. More preferably, the thickening agent is a polymer,preferably a hydrophilic polymer.

A still further aspect of the invention provides a substantiallyhomogenous liquid composition capable of percutaneous delivery of one ormore physiologically active agents, the composition including a volatilesolvent, at least one physiologically active agent and at least twopolymers, one of which is a modulating polymer, wherein the rate ofdelivery of said physiologically active agent is adjustable by varyingthe ratio of said modulating polymer with respect to the active agent. Apreferred ratio of modulating polymer:active is 1-10,000:10,000-1. Theratio will vary according to the potency of the active agent, i.e. howmuch active agent on a mass basis is required to achieve thephysiologically effect desired. For example, for clotrimazole, the ratioof modulating polymer : active agent will be in the order of 1-10:10-1.

A still further aspect of the invention provides a substantiallyhomogenous liquid composition capable of percutaneous delivery of one ormore physiologically active agents, the composition including a volatilesolvent, at least one physiologically active agent and at least twopolymers, one of which is a hydrophobic polymer and one of which is ahydrophilic polymer, wherein the rate of delivery of saidphysiologically active agent is adjustable by varying the ratio of saidhydrophobic polymer with respect to the hydrophilic polymer. A preferredration of hydrophobic polymer: hydrophilic polymer is 1-100:100-1. Amore preferred ration of hydrophobic polymer: hydrophilic polymer is1-10:10-1.

The volatile solvent used in the compositions of the invention may beone or more pharmaceutically or veterinarially acceptable solvents. Thesolvent may be present in an amount of at least 50% w/w.

The compositions of the invention may include one or more skinabsorption/penetration enhancers which enhance the absorption and/orpenetration of the active agent. The absorption/penetration enhancersmay be present in an amount of about 0.1 to 40% w/w of the composition.The absorption/penetration enhancer may be any suitable enhancer knownin the art. The enhancer may be a proton accepting solvent. The rate ofpenetration of the active agent may also be varied by adjusting the rateof release of the penetration enhancer from the polymer.

The composition of the invention may be in the form of a solution or adispersion. The composition may also be in the form of a gel.

Where the composition is in the form of a dispersion, the disperse phasemay be in the form of microparticles, microcapsules, microspheres,microsponges or liposomes which may contain and/or be coated with theactive agent. Where the disperse phase in the form of microparticles,microcapsules, microspheres or liposomes, the continuous phase mayinclude a hydrophobic polymer or a hydrophilic polymer.

The active agent may be dispersed or dissolved in the composition of theinvention and may be present in the composition in a physiologicallyeffective amount. The concentration of active agent used in thecomposition of the invention may be approximately equivalent to thatnormally utilised for that particular agent in conventionalformulations, particularly that used in conventional transdermal patchdelivery systems. The amount of drug to be incorporated in thecomposition varies depending on the particular drug, the desiredtherapeutic effect, and the time span for which the device is to providetherapy. For most drugs, the passage of the drugs through the skin willbe the rate-limiting step in delivery. Thus, the amount of drug and therate of release is typically selected so as to provide transdermaldelivery characterised by a zero order time dependency for a prolongedperiod of time. The minimum amount of drug in the system is selectedbased on the amount of drug which passes through the skin in the timespan for which the device is to provide therapy.

Normally, the amount of drug in the system can vary from about 0.01% w/wto about 50% w/w.

The compositions may include other components such as stabilisers,plasticisers and waterproofing agents.

In yet a further aspect the present invention provides a method for thepercutaneous delivery of an active agent, the method including applyinga percutaneous composition in accordance with the invention to the skinof subject. The composition according to the invention may have an antifungal, anti bacterial or anti viral activity. The subject may be humanor an animal.

In yet a further aspect, the present invention provides a method for theprophylactic or therapeutic treatment of a subject includingpercutaneously delivering an effective amount of an active agent byapplication of a composition in accordance with the present invention tothe skin of the subject. The subject may be human or an animal.

PREFERRED EMBODIMENT OF THE INVENTION

Examples of suitable volatile solvents include skin safe solvents suchas ethanol, isopropanol or acetone.

Preferably the enhancer is a safe, skin-tolerant ester. Particularlypreferred are compounds such as octyl dimethyl para amino benzoate andoctyl methoxycinnamate, isoamyl para amino benzoate, octyl salicylate,glyceryl para amino benzoate, triethanolamine salicylate and octocryleneare expected to be suitable.

The modulating polymer is preferably a substantially non-occlusivefilm-forming polymer, for example an hydroxyalkyl cellulose. Morepreferably the film forming polymer is hydroxypropyl cellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, carbomer, PVM/MAdecadiene cross polymer, hydroxypropylguar, acrylate polymer orcopolymer, alkyl olefinic acid amide/olefinic acid or ester copolymeroctylacrylamide, octylpropenamide acrylate copolymer, aminoalkylmethacrylate copolymer, ammonio methacrylate copolymer, PVP/VAcopolymer, PVA, PVM/MA butylester copolymer, shellac or alkylacrylate/methylmethacrylate copolymer.

The hydrophilic polymer or thickening agent may be selected from anypharmaceutically or veterinarally acceptable polymer. Examples ofsuitable hydrophilic polymer or thickening agent include alkylcelluloseand hydroxyalkyl cellulose. Preferably the hydrophilic polymer orthickening agent is hydroxypropylmethylcellulose, more preferablyhydroxypropylcellulose although other hydrophilic polymers may be used,eg. polyvinylpyrrolidone, carbomer, PVM/MA decadiene cross polymer,hydroxypropylguar etc.

The hydrophobic polymer may be acrylate polymer or copolymer. Preferablythe hydrophobic polymer is a carboxylated acrylic polymer or copolymer.The hydrophobic polymer may also be an alkyl olefinic acidamide/olefinic acid or ester copolymer. The hydrophobic polymer is morepreferably an octylacrylamide, octylpropenamide acrylate copolymer,aminoalkyl methacrylate copolymer, ammonio methacrylate copolymer,PVP/VA copolymer, PVA, PVM/MA butylester copolymer, shellac or alkylacrylate/methylmethacrylate copolymer

The overall polymer content of the composition of the invention may beup to 50% w/w.

The hydrophilic polymer may be present in an amount of up to about 50%w/w in the composition of the invention.

The hydrophilic polymer, or thickening agent may be preferably presentin an amount of about 0.5 to 30% w/w of the composition of theinvention. More preferably, the hydrophilic polymer is present in anamount of 0.05 to 10% w/w of the composition, most preferably 1.0 to5.0% w/w of the composition.

The hydrophobic polymer may be present in an amount up to about 50% w/w.The hydrophobic polymer may be present in an amount of about 0.001 to30% of the composition of the invention. Preferably, the hydrophobicpolymer is present in an amount of 1.0 to 10% of the composition, morepreferably 1.5 to 6.0%.

The active agent may be any suitable compound. The active agent may be apharmaceutical or veterinary agent. The active agent may be a drug thatis normally delivered by oral, parenteral, percutaneous or rectal route.The active agent may be a prodrug.

Examples of active drugs that can be administered by the noveltransdermal drug delivery system of this invention include, but are notlimited to:

Cardioactive medications, for example, organic nitrates such asnitroglycerine, isosorbide dinitrate, and isosorbide mononitrates;quinidine sulfate; procainamide; thiazides such as bendroflumethiazide,chlorothiazide, and hydrochlorothyazide; nifedipine; nicardipine;adrenergic blocking agents, such as timolol and propranolol; verapamil;diltiazem; captopril; clonidine and prazosin.

Androgenic steroids, such as testosterone, methyltestosterone andfluoxymesterone.

Estrogens, such as conjugated estrogens, esterified estrogens,estropipate, 17beta estradiol, 17beta-estradiol valerate, equilin,mestranol, estrone, estriol, 17beta-ethinyl estradiol, anddiethylstilboestrol. Progestational agents, such as progesterone,19-norprogesterone, norethindrone, norethindrone acetate, melengestrol,chlormadinone, ethisterone, medroxyprogesterone acetate,hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel,17alpha hydroxyprogesterone, dydrogesterone, dimethisterone,ethinylestrenol, norgestrel, demegestone, promegestone, and megestrolacetate.

Drugs having an action on the central nervous system, for examplesedatives, hypnotics, antianxiety agents, analgesics and anaesthetics,such as chloral, buprenorphine, naloxone, haloperidol, fluphenazine,pentobarbital, phenobarbital, secobarbital, codeine, lidocaine,tetracaine, dyclonine, dibucaine, methocaine, cocaine, procaine,mepivacaine, bupivacaine, etidocaine, prilocaine, benzocaine, fentanyl,and nicotine.

Nutritional agents, such as vitamins, essential amino adds and essentialfats.

Anti-inflammatory agents, such as hydrocortisone, cortisone,dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone,flurandrenolide, prednisone, halcinonide, methylprednisolone,flurandrenolide, prednisone, halcinonide, methylprednisolone,fludrocortisone, corticosterone, paramethasone, betamethasone,ibuprofen, naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen,ketoprofen, suprofen, indomethacin, piroxicam, aspirin, salicylic acid,diflunisal, methyl salicylate, phenylbutazone, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, and the like.

Antihistamines, such as diphenhydramine, dimenhydrinate, perphenazine,triprolidine, pyrilamine, chlorcyclizine, promethazine, carbinoxamine,tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine,clorprenaline, terfenadine, and chlorpheniramine.

Respiratory agents, such as theophilline and beta2-adrenergic agonistssuch as albuterol, terbutaline, metaproterenol, ritodrine, carbuterol,fenoterol, quinterenol, rimiterol, solmefamol, soterenol, andtetroquinol.

Sympathomimetics, such as dopamine, norepinephrine, phenylpropanolamine,phenylephrine, pseudoephedrine, amphetamine, propylhexedrine andepinephrine. Miotics, such as pilocarpine, and the like. 12. Cholinergicagonists, such as choline, acetylcholine, methacholine, carbachol,bethanechol, pilocarpine, muscarine, and arecoline.

Antimuscarinic or muscarinic cholinergic blocking agents such asatropine, scopolamine, homatropine, methscopolamine, homatropinemethylbromide, methantheline, cyclopentolate, tropicamide,propantheline, anisotropine, dicyclomine, and eucatropine. Mydriatics,such as atropine, cyclopentolate, homatropine, scopolamine, tropicamide,eucatropine and hydroxyamphetamine.

Psychic energizers such as 3-(2-aminopropyl)indole,3-(2-aminobutyl)indole, and the like.

Anti-infectives, such as antibiotics, including penicillin,tetracycline, chloramphenicol, sulfacetamide, sulfamethazine,sulfadiazine, sulfamerazine, sulfamethizole and sulfisoxazole;antivirals, including idoxuridine; antibacterials, such as erythromycinand clarithromycin; and other anti-infectives including nitrofurazoneand the like.

Dermatological agents, such as vitamins A and E.

Humoral agents, such as the prostaglandins, natural and synthetic, forexample PGE1, PGF2alpha, and PGF2alpha, and the PGE1 analog misoprostol.

Antispasmodics, such as atropine, methantheline, papaverine,cinnamedrine, and methscopolamine.

Antidepressant drugs, such as isocarboxazid, phenelzine,tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin,desipramine, nortriptyline, protriptyline, amoxapine, maprotiline, andtrazodone.

Anti-diabetics, such as insulin, and anticancer drugs such as tamoxifenand methotrexate.

Anorectic drugs, such as dextroamphetamine, methamphetamine,phenylpropanolamine, fenfluramine, diethylpropion, mazindol, andphentermine.

Anti-allergenics, such as antazoline, methapyrilene, chlorpheniramine,pyrilamine and pheniramine.

Tranquilizers, such as reserpine, chlorpromazine, and antianxietybenzodiazepines such as alprazolam, chlordiazepoxide, clorazeptate,halazepam, oxazepam, prazepam, clonazepam, flurazepam, triazolam,1orazepam and diazepam.

Antipsychotics, such as thiopropazate, chlorpromazine, triflupromazine,mesoridazine, piperacetazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chlorprathixene,thiothixene, haloperidol, bromperidol, 1oxapine, and molindone.

Decongestants, such as phenylephrine, ephedrine, naphazoline,Antipyretics, such as aspirin, salicylamide, and the like.

Antimigrane agents, such as dihydroergotamine and pizotyline.

Drugs for treating nausea and vomiting, such as chlorpromazine,perphenazine, prochlorperazine, promethazine, triethylperazine,triflupromazine, and trimeprazine.

Anti-malarials, such as the 4-aminoquinolines, alpha-aminoquinolines,chloroquine, and pyrimethamine.

Anti-ulcerative agents, such as misoprostol, omeprazole, and enprostil.

Peptides and proteins, such as drugs for Parkinson's disease,spasticity, and acute muscle spasms, such as levodopa, carbidopa,amantadine, apomorphine, bromocriptine, selegiline (deprenyl),trihexyphenidyl hydrochloride, benztropine mesylate, procyclidinehydrochloride, baclofen, diazepam, dantrolene, insulin, erythropoietinand growth hormone.

Anti-estrogen or hormone agents, such as tamoxifen or human chorionicgonadotropin.

Nucleotides and nucleic acids (eg. DNA).

The active agents can be present in the composition in different forms,depending on which form yields the optimum delivery characteristics.Thus, in the case of drugs, the drug can be in its free base or acidform, or in the form of salts, esters, or any other pharmacologicallyacceptable derivatives, or as components of molecular complexes.

The utility of the invention is described as follows using variousexamples and graphs. The examples are by no means extensive and do notset boundaries for the invention in any way. The purpose of the examplesis to provide evidence of the function of the invention and advantagesthereof.

In the examples provided, the effectiveness of the composition accordingto the invention as a diffusion controlling film is shown. It can bedemonstrated that the system can be used with transdermal penetrationenhancers to modify the transdermal flux rate of active molecules. Itcan also be used with or without penetration enhancers to effectivelyretain active substances on the top layers of skin or to provide asustained rate of release of active into the skin.

Some examples also highlight the ability of the system to provide washresistance.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a plot of the percent of applied dose of Ibuprofen transferredacross shed snake skin in vitro from different gel formulationsaccording to the invention. The error bars represent the SEM.

FIG. 2 is a plot of the percent of the applied dose transferred acrossshed snake skin in vitro from Flurbiprofen gels. The error barsrepresent the SEM. P=0.002 (paired t-test relative to control).

FIG. 3 is a plot of the percent of applied dose of Ketoprofentransferred across shed snake skin in vitro from different gelformulations according to the invention. The error bars represent theSEM.

FIG. 4 is a graph of the percent of applied dose of Canesten™ and aformulation according to the invention retained on the skin after agiven time and under given conditions.

FIG. 5 is a plot of the percent of applied dose transferred across skinin vitro from Ketoprofen gels according to the invention in which thenature of the hydrophobic polymer has been altered. The error barsrepresent the SEM.

FIG. 6 is a plot of the percent of applied dose transferred across skinin vitro from Diclofenac gels according to the invention.

EXAMPLE A

A composition in accordance with the invention was prepared by combiningthe following components in a stirred vessel at ambient temperature:

Component Amount (w/w) Ketoprofen 2.5% Klucel (hydroxypropyl cellulose)3.0% Acrylate/octylpropenamide copolymer 3.8% Alcohol 100 90.7%

The composition formed was in the form of a clear solution. When appliedto the skin and spread out on the skin surface formed a substantiallyclear thin film.

EXAMPLE B

Component Amount (w/w) Ketoprofen 2.5% Klucel (hydroxypropyl cellulose)2.5% Acrylate/octylpropenamide copolymer 3.0% * Benzyl Benzoate 3.0%Alcohol to 100% * enhancer

EXAMPLE C

Component Amount (w/w) Ibuprofen 2.5% Klucel G 3.0% Ethanol to 100%

In Vitro Diffusion Measurements

Shed Snake Skin.

The Children's Python shed snake skin was obtained during naturalshedding and the dorsal skin was used. Shed snake skin has shown to be asuitable model membrane for human skin by Itoh, et al., Use of ShedSnake Skin as a Model Membrane for In Vitro Percutaneous PenetrationStudies: Comparison with Human Skin Pharm. Res., 7 (10), 1042-1047,1990; and Rigg, et al; Shed Snake Skin and Hairless Mousse Skin as ModelMembranes for Human Skin During Permeation Studies, J. Invest.Dermatol., 94; 235-240, 1990.

Method of Conducting In-Vitro Skin Diffusion Experiments in HorizontalDiffusion Cells

A modified stainless steel flow-through diffusion cell assembly based onthat first shown by Cooper in J. Pharm. Sci. 73, 1984, was used toperform the experiments on diffusion of the drugs from various donorcompositions through snake skin.

Topical formulations are weighed out onto the skin substrate which hasan area of 0.79 cm². Active substance penetrates through the skin andinto the receptor solution in the bottom section of the cell. Inlet andoutlet tubes connected to the receptor chamber maintain skin conditions.

The temperature of the skin was maintained at 32° C.

The receptor solution consisted of 50% propylene glycol in water, madeisotonic with 0.9% sodium chloride and preserved with 0.1% sodium azide.

The concentration of applied drug in each diffusion cell sample wasmeasured using high pressure liquid chromatography (HPLC) and absorbancedetection. The results reported for each experiment are average valuesof the replicate diffusion cells. The assay conditions used for eachdifferent drug are given in each example.

EXAMPLE 1

The in vitro diffusion cell method described above was used todemonstrate that ibuprofen penetrates through skin using this system.The formulations tested are described in the table below.

Gel 1 Gel 2 Gel 3 Control Material % w/w % w/w % w/w % w/w Ibuprofen 5.05.0 5.0 5.0 Octyl Salicylate 5.0 3.0 5.0 3.0 Hydroxypropyl 2.2 2.2 2.22.2 Cellulose Dermacryl ™ 79 0.001 0.001 0.001 Water — 20.0 15.0 23.8Ethanol to 100.0 to 100.0 to 100.0 to 100.0 N.B.Dermacryl^( ™ 79 = Acrylates/t-octylpropenamide copolymer)

Samples were assayed as per the method described earlier.

The detection wavelength was 210 nm and the mobile phase consisted of60% acetonitrile, 0.1% H₃PO₄, pH=3 adjusted with NaOH.

FIG. 1 shows the plot of percent dose transferred versus time for therespective formulations. Error bars represent the standard error of themean.

EXAMPLE 2

The same in-vitro diffusion cell method described was also used todemonstrate that flurbiprofen (another NSAID) penetrates skin from thissystem.

The following formulations were tested:

Control F65/57/02 Material % w/w % w/w Flurbiprofen 5.0 5.0 Dermacryl ™79 0.001 0.001 Hydroxypropyl 2.2 2.2 Cellulose Octyl Salicylate — 5.0Deionised Water 15.0 15.0 Ethanol 95% 77.7 72.7

Samples were assayed according to the general procedure outlinedearlier.

The detection wavelength was 247 nm and the mobile phase consisted of60% acetonitrile, 0.1% H₃PO₄ at pH 3 adjusted with NaOH.

FIG. 2 shows the plot of % dose transferred versus time for theformulations. Error bars represent the standard error of the mean.

EXAMPLE 3

In vitro penetration studies were used to demonstrate that ketoprofenpenetrates skin and that the rate of penetration could be modified byinclusion of higher levels of Dermacryl™ 79.

The formulations tested were as follows:

71/05/01 71/05/02 71/05/03 71/05/04 71/05/05 Material % w/w % w/w % w/w% w/w % w/w Ketoprofen 2.5 5.0 2.5 2.5 2.5 Octyl 2.5 5.0 2.5 2.5 —Salicylate Derm- 0.05 0.05 2.5 10.0 0.05 acryl ™ 79 Klucel ™ 2.2 2.2 2.22.2 2.2 Ethanol 95% to 100.0 to 100.0 to 100.0 to 100.0 to 100.0

FIG. 3 shows the plot of % dose transferred versus time for eachformulation. This shows that by adjusting the ratio of the modulatingpolymer:active and/or hydrophobic polymer:hydrophilic polymer, the rateof the release of Ketoprofen into the skin of the subject can be varied.In particular, the graph demonstrates that the penetration enhancementcan be controlled by varying the level of Dermacryl™ 79 in the gel.

Samples were assayed according to the general procedure outlinedearlier. The detection wavelength was 255 nm and the mobile phaseconsisted of 55% acetonitrile, 0.1% H₃PO₄ at pH 3 adjusted with NaOH.

EXAMPLE 4

In order to demonstrate the ability of the composition according to theinvention to produce water resistant films capable of increasing theskin substantivity of actives the following testing was conducted.

An in vivo experiment was conducted on a 1% clotrimazole gel accordingto the invention versus commercial clotrimazole cream (1% clotrimazole)to test for substantivity and wash resistance.

The gel formulation according to the invention was as follows:

2.5% w/w Klucel™ (Hydroxypropylcellulose)

3.2% w/w Dermacryl™ 79 (Acrylates/octylpropenamide copolymer)

1.0% w/w Clotrimazole

to 100% w/w Ethanol

Each product was applied to the forearm of the subject and allowed todry thoroughly.

At 6 and 24 hours after application the active remaining on the skin wasextracted using warm ethanol.

A further condition used was a thirty second immersion in a soapsolution at the 10 hour time point.

The results of the trial are depicted in FIG. 4.

The results clearly demonstrate that significantly more clotrimazoleremains on the skin after application of the gel compared with thecommercial clotrimazole cream.

In fact greater than 50% of clotrimazole originally applied is stillpresent after 24 hours compared with approximately 5% for the commercialclotrimazole cream.

Further, the results demonstrate the wash resistance of the gel.

The soaking of the film removed only a small portion of clotrimazolefrom the gel formulation whereas after soaking the commercialclotrimazole cream, only about 1% of the original dose of clotrimazoleremained.

EXAMPLE 5

To demonstrate the activity of clotrimazole in the gel formulationaccording to the invention after application the following experimentwas conducted.

A series of 1% clotrimazole gels prepared according to the invention anda commercial 1% clotrimazole cream were subjected to a zone ofinhibition test against Candida albicans.

The gels and cream were applied to round glass cover slips of 5 cm²each. The application rate for all products was 5 mg/cm².

After drying, the coated side of the slides were placed on MEA plateswhich had been previously seeded with a culture of C. albicans. Theplates were incubated at 37° C. for 72 hours. The zone of inhibition wasmeasured around the test slides at the end of the incubation period.Furthermore the slides were removed and an assessment of the growth ofthe test organism was made in the contact zone with the slide. All testswere performed in duplicate.

The formulations tested were as follows:

F65/22/02 F65/22/01 F65/53/01 F65/53/02 Material % w/w % w/w % w/w % w/wClotrimazole — 1.00 1.00 — Klucel ™ 2.50 2.50 2.50 2.50 Dermacryl ™ 3.203.20 — — 79 Propylene — — 5.00 5.00 Glycol Ethanol to 100.0 to 100.0 to100.0 to 100.0

The results of the testing are shown in the following table.

Inhibition in Contact Sample Description Zone Zone mm A commercial 1%Almost Complete 1, 1 clotrimazole Cream B.6C04 Exp. 3/98 PlaceboClotrimazole Gel No Inhibition 0, 0 Form No. F65/22/02 B/N E65/22/02Clotrimazole 1% Gel Form Almost Complete 4, 4 No. F65/22/01 B/NE65/22/01 Clotrimazole 1% Gel Form Complete 8, 9 No. 65/53/01 PlaceboGel F65/53/02 Partial 0, 0

The results clearly demonstrate that the clotrimazole is biologicallyactive within the film according to the invention and in fact is moreactive than the commercial clotrimazole cream.

Further, the activity of clotrimazole could be increased by addition ofa plasticiser ie., propylene glycol.

EXAMPLE 6

As a demonstration of the ability to use a variety of thickeners in thisinvention the following formulations were prepared.

F71/37/06 F71/37/07 F71/37/10 F71/37/11 F71/37/13 F71/57/01 Material %w/w % w/w % w/w % w/w % w/w % w/w Carbopol ™ Ultrez 10 0.3 0.5 — — — —Triethanolamine 0.3 — 0.4 — — — PVP/VA 335 (50%) 6.0 — 6.0 — 6.0 —Deionised Water 30.0 20.0 30.0 — 30.0 20.0 Tributylamine — 0.7 — — — —Eudragit ™ E — 3.0 — — — 3.0 Stabileze ™ 06 — — 0.7 2.0 — — Eudragit ™RL PO — — — 3.0 — — Ethomeen ™ C25 — — — 4.0 — — Hydroxypropyl- — — — —2.50 — methylcellulose Jaguar ™ HP-120 — — — — — 2.0 Citric Acid — — — —— 0.055 Ethanol 95% to 100.0 to 100.0 to 100.0 to 100.0 to 100.0 to100.0 Carbopol ™ Ultrez10 = Carbomer PVP/VA 335 = 50% solution of PVP/VAEudragit ™ E = Aminoalkyl methacrylate copolymer Stabileze ™ 06 = PVM/MAdecadiene cross polymer Eudragit ™ RLPO = Ammonio Methacrylate CopolymerEthomeen ™ C25 = PEG 15 Cocamine Jaguar ™ HP-120 = Hydroxypropyl guar

The respective viscosities of the gels made according to the inventionwas measured at 25° C. with a Brookfield RVT viscometer.

They were as follows:

Viscosity (F71/37/06, spindle 3, 10 rpm)=2,500 cps.

Viscosity (F71/37/07, spindle 5, 2.5 rpm)=112,000 cps.

Viscosity (F71/37/10, spindle 4, 5 rpm)=76,000 cps.

Viscosity (F71/37/11, spindle 4, 2.5 rpm)=40,800 cps.

Viscosity (F71/37/13, spindle 6, 5 rpm)=102,000 cps.

Viscosity (F71/57/01, Spindle 4, 10 rpm)=10,000 cps.

These viscosity measurements demonstrate that various thickeners can beused to produce suitable gels with a variety of hydrophobic polymers.

EXAMPLE 7 Comparative Example

The gel described by Shionogi, U.S. Pat. 4,935,241 dated Jun. 19, 1990,and entitled Pharmaceutical Preparation for Tinea Pedis has acosmetically unacceptable base due to:

Lack of viscosity from ethyl cellulose making it difficult to apply.

Incompatibility between HPC or HPMC and EA/MMA.

In order to overcome these shortcomings a gel was prepared usingHydroxypropylcellulose and a compatible polymer, Dermacryl™ 79.

This product had the advantage of:

Complete miscibility between the two polymers in solution (HPC andDermacryl™ 79).

The gel could be prepared at a large range of viscosities ie, from 100cps to 200,000 cps depending on molecular weight and percentage of HPCused.

Hence this product had the advantage of both clarity, homogeneity andease of application.

To test the utility of the adapted gel formulation to deliver activesinto skin an in-vitro skin absorption experiment was conducted comparingthe absorption of clotrimazole (an antifungal) from the compositionaccording to the invention™, Shionogi base and A commercial clotrimazolecream™ cream. All preparations contained 1% clotrimazole.

The gel formulations used are shown below.

Shionogi Base F65/64/01 F71/17/02 Material % w/w % w/w Clotrimazole 1.001.00 Klucel ™ 2.50 — Dermacryl ™ 79 3.20 — Ethyl Cellulose — 1.00Eudragit ™ NE40D — 10.0 Ethanol 95% to 100.0 to 100.0 Eudragit ™ NE 40D= 40% dispersion of ethylacrylate/methyl-methacrylate

These formulations were compared for skin penetration, and epidermal anddermal retention using the following procedure.

Clotrimazole Test Method and Table of Results

Method:

Equipment & Materials:

in-vitro Franz diffusion cell with full thickness human skin (surfacearea 1.23 cm², receptor volume 3.5 ml)

HPLC equipment: Shimadzu automated HPLC system with UV detection

bovine serum albumin (BSA) dissolved in phosphate buffered saline (pH7.4) as receptor phase to mimic physiological conditions.

Experimental Protocol:

finite dosing (50 mg of each formulation)

receptor phase: 4% BSA in PBS at pH 7.4

sampling time: 0, 6, 10 and 24 hours (amount in receptor phase)

epidermis separated from the dermis following 24 hour exposure toformulation

non occlusive study

each time period and formulation conducted in triplicate

Application Procedure

50 mg of each formulation was applied to the exposed skin surface attime 0 min

Procedure was the same for all products

HPLC Assay

Active content determined by HPLC assay using a detection wavelength of210 mm.

The following table shows cumulated clotrimazole concentration inreceptor phase (μg/cell) at 0, 6, 10 and 24 hours and in the epidermisand dermis (μg/cm2) following application of clotrimazole gels(F65/64/01 and F71/17/02) and a commercial clotrimazole cream.

Receptor Epidermis Dermis Formulation 0 hrs 6 hrs 10 hrs 24 hrs at 24hrs at 24 hrs 1. The composition according to the invention (F65/64/01)1A N N N N 114.23  1.72 1B N N N N 64.01 2.37 1C N N N N 69.89 2.60 Mean± Standard 82.71 ± 27.45 2.23 ± 0.46 Deviation 2. Clotrimazole Gel(Shionogi base) (F71/17/02) 2A N N N N 19.10 2.49 2B N N N N 23.29 2.332C N N N N 28.67 1.99 Mean ± Standard 23.69 ± 4.79  2.27 ± 0.26Deviation 3. Commercial 1% clotrimazole cream 3A N N N N  8.66 0.92 3B NN N N 18.66 1.39 3C N N N N 13.88 0.86 Mean ± Standard 13.74 ± 5.0  1.06± 0.29 Deviation N = Not Detectable

Statistical Analysis

Epidermal and dermal retention of clotrimazole following applications ofeach of the formulations was compared by oneway ANOVA with posthocfollow-up using Tukey-HSD (sig p<0.05).

Epidermal retention: Formulation 1 (clotrimazole gel F65/64/01)demonstrated significantly greater epidermal retention of clotrimazolethan the other formulations tested.

Dermal retention: Formulations 1 and 2 (clotrimazole gels) demonstratedsignificantly greater dermal retention of clotrimazole than thecommercial clotrimazole cream.

The following observations were thus made:

1. None of the formulations tested had detectable skin penetration tothe receptor phase up to and including at 24 hours followingapplication.

2. The epidermal concentrations of clotrimazole in decreasing order wereFormulation 1 (F65/64/01—a product according to the invention),Formulation 2 (F71/17/02—Shionogi base) and Formulation 3 (commercial 1%clotrimazole cream). The epidermal retention of formulation 1 wassignificantly greater than that of the other two formulations tested.

3. The dermal concentrations of formulation 1 and 2 were similar andwere significantly higher than that of the commercial clotrimazolecream.

These results were surprising and clearly demonstrate the superiority ofthe composition according to the invention system to deliver moreclotrimazole into skin over a 24 hour period. Also the compositionaccording to the invention was far more effective than a commercialcream for delivery of clotrimazole.

This work coupled with results shown in example 4 demonstrate that thecompositions according to the invention are not only more substantive totop layers of skin but also deliver more active into skin than thecommercial clotrimazole cream.

EXAMPLE 8

To demonstrate the ability of a range of hydrophobic polymers to modifythe penetration of actives through skin the following experimentationwas conducted.

Six different hydrophobic polymers were prepared in a base compositionaccording to the invention using ketoprofen as the active and octylsalicylate as the penetration enhancer.

These were tested for in-vitro transdermal penetration using baby snakeskin as described previously.

The following formulations were prepared:

F71/24/01 F71/24/02 F71/24/03 F71/24/04 Material % w/w % w/w % w/w % w/wKetoprofen 2.50 2.50 2.50 2.50 Octyl 2.50 2.50 2.50 — SalicylateKlucel ™ 2.20 2.20 2.20 2.20 PVP/VA 20.0 — — — (50%) Eudragit ™ E — 10.0— — Shellac — — 10.0 — Dermacryl ™ — — — 10.0 79 Ethanol 95% to 100.0 to100.0 to 100.0 to 100.0 F71/24/05 F71/24/06 F71/24/07 F71/24/08 Material% w/w % w/w % w/w % w/w Ketoprofen 2.50 2.50 2.50 2.50 Octyl 2.50 2.502.50 2.50 Salicylate Klucel ™ M — 2.20 2.20 2.20 Klucel ™ JFF 12.20  — —— Amphomer ® — — 10.00  — Gantrez ™ — — — 20.0  ES 425 (50%) Ethanol 95%to 100.0 to 100.0 to 100.0 to 100.0 Klucel ™ = HydroxypropylcelluloseAmphomer ™ = Octylacrylamide/acrylates/butylaminoethyl methacrylatecopolymer Gantrez ™ ES 425 = Butyl ester of PVM/MA copolymer

The results of penetration from these gels are shown graphically in FIG.5 wherein the % dose transferred is plotted versus time.

These results demonstrate that the penetration of ketoprofen can becontrolled through the incorporation of hydrophobic polymers.

EXAMPLE 9

This example demonstrates that the composition according to theinvention may also be used as a vehicle for anti-viral compounds. Theactive in this case was penciclovir. A gel was prepared according to thefollowing formulation.

% w/w Penciclovir 0.30 Dermacryl ™ 79 3.0 N methyl pyrrolidone 30.0Klucel ™ M 2.20 Deionised Water 14.50 Isopropyl alcohol 50.0

This product was a clear viscous, colourless, homogenous gel suitablefor application to skin to produce a localised anti-viral effect.

EXAMPLE 10

To further demonstrate the utility of the composition according to theinvention for delivering NSAID's through skin, the in-vitro diffusioncell method described previously was used to assess penetration ofdiclofenac.

The following formulations were tested.

Control Solution F63/55/01 Material % w/w % w/w Dermacryl ™ 79 — 0.001Klucel ™ — 2.20 Octyl Dimethyl PABA — 1.16 Diclofenac  1.16 1.16Diethylammonium Water 30.0  — Ethanol to 100.0 to 100.0

The skin penetration results from the formulations are shown graphicallyin FIG. 6.

EXAMPLE 11 Comparative Description of Shionogi patent Gels

The purpose of this example is to demonstrate that the gels of U.S. Pat.No. 4,935,241 dated Jun. 19, 1990, and entitled “PharmaceuticalPreparation for Tinea Pedis” do not meet the criteria of thecompositions according to the invention, i.e homogeneity during storage.

F71/46/04 F71/46/05 F71/46/06 Material % w/w % w/w % w/w Ethyl Cellulose 1.00 — — EA/MMA 10.00 10.00 10.00 (40% dispersion) Hydroxypropyl- — 1.00 — methylcellulose Hydroxypropylcellulose — —  1.00 Deionised water22.20 22.20 22.20 Isopropyl alcohol to 100.0 to 100.0 to 100.0

Appearance of gels after one week of storage at room temperature was asfollows.

F71/46/04

Thin clear gel with a fine flocculated precipitate which had settled onbottom.

F71/46/05

Translucent, thin, lumpy gel with some solid white lumps.

F71/46/06

Clear gel which separated into two clear layers.

Although specific embodiments of the invention have been describedabove, it will be clear to the skilled reader that the invention is notrestricted to these particular embodiments and the variations andmodifications of the invention as particularly described may be madewithout departing from the scope of the present invention.

The claims defining the invention are as follows:
 1. A substantiallyhomogenous liquid composition capable of percutaneous delivery of onemore physiologically active agents, the composition comprising at leastone physiologically active agent, a volatile solvent, and a ratemodulating carrier, said rate modulating carrier consisting essentiallyof (i) a hydrophilic polymer selected from the group consisting ofhydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolldone, carbomer, PVM/MA decadiene cross polymer andhydroxypropylguar and copolymers thereof, said hydrophilic polymer beingpresent in an amount of from 0.001 to 50% w/w of the total liquidcomposition and (ii) a hydrophobic polymer selected from the groupconsisting of octylacrylamide, octylpropenamide acrylate copolymer,aminoalkyl methacrylate copolymer, ammonio methacrylate copolymer,PVP/VA copolymer, PVA, PVM/MA butylester copolymer, shellac and alkylacrylates and copolymers thereof, said hydrophobic polymer being presentin an amount of from 0.001 to 50% w/w of the total liquid composition,the combination of hydrophilic and hydrophobic polymers being selectedto enable modulation of the rate of delivery of said physiologicallyactive ingredient.
 2. A liquid composition as claimed in claim 1 whereinupon application to the skin of a subject the hydrophilic polymer formsa continuous phase, and the hydrophobic polymer is dispersed or solubletherein.
 3. A liquid composition as claimed in claim 1 wherein uponapplication to the skin of a subject the hydrophobic polymer forms acontinuous phase, and the hydrophilic polymer is dispersed or solubletherein.
 4. A liquid composition as claimed in claim 2 wherein uponapplication to the skin of a subject said physiologically active agentis contained in said continuous phase.
 5. A liquid composition asclaimed in claim 2 which is in the form of a dispersion and wherein uponapplication to the skin of a subject said physiologically active agentis contained in said dispersed phase.
 6. A liquid composition as claimedin claim 3 wherein upon application to the skin of a subject saidphysiologically active agent is contained in said continuous phase.
 7. Aliquid composition as claimed in claim 3 which is in the form of adispersion and wherein upon application to the skin of a subject saidphysiologically active agent is contained in said dispersed phase.
 8. Aliquid composition as claimed in claim 1 wherein said hydrophilicpolymer is hydroxyalkyl cellulose.
 9. A liquid composition as claimed inclaim 8 wherein said hydrophilic polymer is hydroxypropyl cellulose. 10.A liquid composition as claimed in claim 1 wherein said hydrophobicpolymer is an octyl acrylamide or octylpropenamide acrylate coplymer.11. A liquid composition as claimed in claim 1 further comprising athickening agent, said thickening agent excluding ethyl cellulose.
 12. Aliquid composition as claimed in claim 11 wherein said thickening agentis a polymer soluble in both alcohol and water.
 13. A liquid compositionaccording to claim 1 wherein the rate of delivery of saidphysiologically active agent is adjustable by varying the ratio of saidrate modulating carrier to active agent.
 14. A liquid composition asclaimed in claim 13 further comprising a penetration enhancer, thequantity of which may be adjusted with respect to the quantity ofhydrophilic and hydrophobic polymers and the active agent to alter therate of delivery of said physiologically active agent.
 15. A liquidcomposition according to claim 1 wherein the rate of delivery of saidphysiologically active agent is adjustable by varying the ratio of saidhydrophilic and hydrophobic polymers with respect to each other.
 16. Aliquid composition according to claim 15 wherein said hydrophilicpolymer is hydroxyalkyl cellulose.
 17. A liquid composition according toclaim 16 wherein said hydrophilic polymer is hydroxypropyl cellulose.18. A liquid composition according to claim 15 wherein said hydrophobicpolymer is an octyl acrylamide or octylpropenamide acrylate copolymer.19. A method of percutaneous delivery of an active agent, the methodincluding applying a liquid composition as claimed in claim 1 to theskin of a subject.
 20. A method as claimed in claim 19 wherein saidsubject is animal.
 21. A method of prophylactic or therapeuticantimicrobial, antifungal or antiviral treatment including administeringto a patient requiring such treatment an effective amount of a liquidcomposition as claimed in claim 1.